The major excitatory neurotransmitters in the central nervous system is L-glutamine and L-aspartate. Classification of the excitatory receptors include the AMPA, kainate and NMDA receptors. The NMDA receptor is located on the neuronal cell surface and is composed of multiple binding sites which regulate Ca++ homeostasis. The glycine and glutamate binding sites are allosterically linked at the NMDA receptor complex. Glutamate is the principal excitatory neurotransmitter in the brain and has an integral role in neurologic function including cognition, memory, movement and sensation. Glutamate has also been implicated in the pathogenesis of multiple acute and chronic neurological diseases.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a known pharmaceutical compound and is described in U.S. Pat. No. 2,884,444. Felbamate has multiple actions on the nerve cell of which one is a glycine site antagonist at the NMDA receptor. See U.S. Pat. Nos. 4,978,680; 5,082,861; 5,292,772; 4,868,327; and 5,256,690.
Felbamate is a modulator of NMDA function by a glycine site antagonist mechanism but has multiple mechanisms of action. These include interaction at the AMPA/kainate receptor, facilitating GABA function, modulation of the Na+ channel, interaction at both of the metabotropic and muscarinic receptors, as well as the L-type calcium channel.
Excessive stimulation of the NMDA receptor by excitatory amino acids or neurotoxic mediators of inflammation is believed to be the etiology of multiple acute and chronic neurological diseases. Sudden toxic elevations of glutamate in acute neurological disorders or increased nerve cell vulnerability by abnormal bioenergetic metabolism in chronic disorders are possible mechanisms. Thus, NMDA exictotoxicity may represent a final common pathway for neuronal death in both acute and chronic neurological disease.
Subsequent to the approval of Felbamate, in 1994 there were reports of aplastic anemia and hepatic failure. These adverse events may have been due to drug interaction.